U.S. patent number 6,093,167 [Application Number 08/876,738] was granted by the patent office on 2000-07-25 for system for pancreatic stimulation and glucose measurement.
This patent grant is currently assigned to Medtronic, Inc.. Invention is credited to Richard P. M. Houben, Alexis C. M. Renirie, Koen J. Weijand.
United States Patent |
6,093,167 |
Houben , et al. |
July 25, 2000 |
System for pancreatic stimulation and glucose measurement
Abstract
There is provided an implantable system and method for
monitoring pancreatic beta cell electrical activity in a patient in
order to obtain a measure of a patient's insulin demand and blood
glucose level. A stimulus generator is controlled to deliver
stimulus pulses so as to synchronize pancreatic beta cell
depolarization, thereby producing an enhanced electrical signal
which is sensed and processed. In a specific embodiment, the signal
is processed to determine the start and end of beta cell
depolarization, from which the depolarization duration is obtained.
In order to reduce cardiac interference, each stimulus pulse is
timed to be offset from the QRS signal which can interfere with the
pancreas sensing. Additionally, the beta cell signals are processed
by a correction circuit, e.g., an adaptive filter, to remove QRS
artifacts, as well as artifacts from other sources, such as
respiration. The thus obtained insulin demand signal is used either
to control delivery of insulin from an implanted insulin pump, or
to control ongoing pancreatic stimulation of a form to enhance
insulin production.
Inventors: |
Houben; Richard P. M. (Berg
& Terblijt, NL), Renirie; Alexis C. M. (Berg en
Dal, NL), Weijand; Koen J. (Hoensbroek,
NL) |
Assignee: |
Medtronic, Inc. (Minneapolis,
MN)
|
Family
ID: |
25368465 |
Appl.
No.: |
08/876,738 |
Filed: |
June 16, 1997 |
Current U.S.
Class: |
604/66;
600/365 |
Current CPC
Class: |
A61B
5/14532 (20130101); A61B 5/7207 (20130101); A61N
1/36007 (20130101); A61B 5/425 (20130101) |
Current International
Class: |
A61B
5/00 (20060101); A61N 1/36 (20060101); A61M
031/00 () |
Field of
Search: |
;604/65-67 ;607/72
;600/345,347,365 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
"Kinetics of Intraperitoneally Infused Insulin in Rats--Functional
Implications for the Bioartificial Pancreas"--Paul De Vos et al.
(Diabetes, vol. 45, Aug. 1996). .
"Pancreatic B Cells Are Bursting, But How?"--Daniel L. Cook et al.
(TINS, vol. 14, No. 9, 1991)..
|
Primary Examiner: McDermott; Corrine
Attorney, Agent or Firm: Woods; Thomas F. Patton; Harold
Jaro; Michael J.
Claims
We claim:
1. A system for sensing insulin demand of a patient,
comprising:
stimulating means for delivering stimulating pulses to the pancreas
of said
patient;
sensing means for sensing the electrical responses of said pancreas
to said stimulating pulses and obtaining signals representative of
said responses; and
processing means for processing said signals and deriving therefrom
a measure of the insulin demand of said patient.
2. The system as described in claim 1, wherein said processing
means comprises first means for obtaining data representative of
the duration of the depolarization burst of pancreatic beta-cells
following delivery of a said stimulating pulse.
3. The system as described in claim 2, comprising heart sensing
means for sensing cardiac signals from said patient, and control
means responsive to said cardiac signals for controlling said
stimulating means to deliver each said stimulus pulse at a time
substantially free of cardiac signal interference, thereby
enhancing detection of said burst duration.
4. The system as described in claim 3, comprising R-wave means for
determining the occurrence of cardiac QRS complexes, and wherein
said control means comprises timing means for timing a next
stimulating pulse at a predetermined delay following the last said
QRS complex, thereby enhancing detection of the onset of said
burst.
5. The system as described in claim 1, comprising initiate means
for automatically controlling said stimulating means to initiate
delivering of stimulus pulses on a predetermined timing
schedule.
6. The system as described in claim 1, comprising external means
for sending signals from an external location to enable said
stimulating means to deliver stimulus pulses.
7. The system as described in claim 1, wherein said stimulating
means comprises electrodes positionable with respect to said
patient's pancreas so as to deliver stimulus pulses and to sense
electrical activity of a plurality of islets of Langerhans within
the patient's pancreas.
8. The system as described in claim 1, wherein said processing
means comprises means for determining the duty cycle of the
depolarization burst of pancreatic beta-cells following a delivered
stimulus pulse.
9. The system as described in claim 1, wherein said processing
means comprises means for determining a measure of the spike
frequency of the depolarization burst of pancreatic beta-cells
following a delivered stimulus pulse.
10. The system as described in claim 1, wherein said processing
means comprises data storage means for storing data representative
of said signals for a plurality of stimulus pulses, and means for
deriving said insulin demand measure as a function of said stored
data.
11. The system as described in claim 1, comprising timing means for
timing delivery of a said stimulating pulse to occur during a
period of pancreatic beta cell repolarization.
12. A system for providing improved sensing of pancreatic beta
cells, whereby to obtain information representative of patient
insulin demand, comprising:
stimulating means for generating and delivering stimulus pulses to
a predetermined patient location;
sensing means for sensing electrical activity of pancreatic beta
cells within said patient, said sensing means being operatively
coordinated with said stimulating means so as to sense beta cell
responses following said stimulus pulses; and
processing means for processing said signals and deriving therefrom
a measure of the insulin demand of said patient,
wherein said stimulating means comprises pancreas delivery means
for delivering said stimulus pulses to the patient's pancreas.
13. The system as described in claim 12, wherein said pancreas
delivery means comprises plural electrode pairs at different
pancreatic location.
Description
FIELD OF THE INVENTION
This invention relates to systems for treatment of
non-insulin-dependent diabetes mellitus and, in particular, systems
for stimulating the pancreas to enhance sensing of beta-cell
electrical activity, from which a measure of patient blood glucose
level is obtained.
BACKGROUND OF THE INVENTION
It is known, from statistics published in 1995, that the number of
diabetes patients in the United States is 7.8 million, or about
3.4% of the total U.S. population. This number has been steadily
rising over the last 25 years. Approximately 90%, or about 7
million, are non-insulin-dependent diabetes mellitus (NIDDM)
patients, in whom the sensitivity to rising glucose levels, or the
responsiveness of insulin, is compromised to varying degrees. About
30%, or 2.3 million these patients, use insulin, and about 25% of
these insulin users take daily measures of blood glucose levels. As
a general proposition, most NIDDM patients are candidates for blood
glucose level measurements and/or injections of supplemental
insulin. The percentage of NIDDM patients receiving insulin
treatment increases with the duration of NIDDM, from an initial
rate of about 25% to about 60% after 20 years. For this population
of patients, there is a need for a flexible and reliable system and
method for measuring glucose level and supplying insulin when and
as needed.
The human pancreas normally provides insulin for metabolic control.
Basically, the insulin acts to promote transport of glucose in body
cells. The pancreas has an endocrine portion which, among other
functions, continuously monitors absolute blood glucose values and
responds by production of insulin as necessary. The
insulin-producing cells are beta cells, which are organized with
other endocrine cells in islets of Langerhans; roughly 60-80% of
the cells in an islet are such beta cells. The islets of Langerhans
in turn are distributed in the pancreatic tissue, with islets
varying in size from only about 40 cells to about 5,000 cells.
It has been observed that neighbor beta cells within an islet are
coupled by gap junctions, which allow for electrical coupling and
communication between neighboring beta cells. The beta cells within
the islet undergo periodic depolarization, which is manifested in
oscillatory electrical spikes produced by the beta cells, often
referred to as a burst which carries on for a number of seconds.
The beta cell electrical activity is characterized by a low
frequency alternation consisting of a depolarized phase (the burst)
followed by a repolarized or hyperpolarized phase which is
electrically silent. The relative time spent in the depolarized
phase, during which the relatively higher frequency beta cell
action potentials are triggered, has a sigmoidal relation with
blood glucose concentration. The duty cycle, or depolarization
portion compared to the quiet portion, is indicative of glucose
level, and thus of insulin demand. Additionally, the frequency of
the spikes during the active period, and likewise the naturally
occurring frequency of the bursts (also referred to plateaus)
carries information reflective of glucose level.
In view of the above, it is to be seen that sensing of the beta
cell activity from islets of Langerhans in the pancreas may provide
information for sensing insulin demand and controlling insulin
delivery. Systems which seek to utilize glucose-sensitive living
cells, such as beta cells, to monitor blood glucose levels, are
known in the art. U.S. Pat. No. 5,190,041 discloses capsules
containing glucose-sensitive cells such as pancreatic beta cells,
and electrodes for detecting electrical activity. The capsules are
situated similarly to endogenous insulin-secreting
glucose-sensitive cells, and signals therefrom are detected and
interpreted to give a reading representative of blood glucose
levels. However, in this and other similar systems, the problem is
in reliably sensing the beta cell electrical activity. It is
difficult to determine the onset of the burst phase, and accurate
determination of the spike frequency is difficult. This sensing
problem is aggravated by cardiac electrical interference, as
sensing of the QRS can mask portions of the islet electrical
activity, particularly the onset of the burst depolarization phase.
Thus, there is a need for a system which effectively and reliably
utilizes the body's own glucosemonitoring system for obtaining
accurate information concerning blood glucose level and insulin
demand. Additionally, it is very desirable to provide for an
effective response to rising insulin demand by activating an
insulin pump, or by enhancing pancreatic insulin production.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a system for improved
sensing of pancreatic beta cell electrical activity, so as to
determine insulin demand, i.e., blood glucose level. The system
includes a stimulus generator for stimulating the pancreatic beta
cells with electric field stimuli so as to provide synchronized
burst responses which are relatively free of signal interference
and which can be accurately timed. It is a further object of this
invention to provide systems for sensing insulin demand and for
responding by delivering insulin from a pump, or by stimulating the
pancreas to cause increased insulin production by the pancreas (as
disclosed in concurrently filed application Ser. No. 08/876,610
case P-7328, incorporated herein by reference).
In view of the above objects, there is provided a system and method
for improved insulin delivery for an NIDDM patient. The system is
based on sensing in-vivo pancreatic beta cell electrical activity,
as an indictor for insulin demand. In a first embodiment, a
pancreatic stimulus generator is controlled to deliver synchronized
stimulus pulses, i.e., electric field stimuli, to the patient's
pancreas at a slow rate, e.g., once every 6-20 seconds. Following a
generated electric field stimulus, the depolarization activity of
the cells is sensed and processed to derive an indication of blood
glucose level. The system monitors cardiac activity, and controls
the delivery of stimulus pulses so that the onset of each beta cell
burst is relatively free of interference of the heart's QRS
complex. The blood level information obtained from the sensed beta
cell activity can be used for automatic control of an insulin pump.
In another embodiment, the electric field stimuli are delivered to
transplanted pancreatic beta cells in order to enhance insulin
production, as disclosed in referenced Ser. No. 08/876,610. In yet
another embodiment, the vagal nerve is stimulated to
synchronize.
The blood glucose level monitoring may be carried out substantially
continuously by an implantable system, or the system may be
programmed for periodic measurement and response. In another
embodiment, measurements may initiated by application of an
external programmer, e.g., a simple hand-held magnet. In yet
another embodiment of the invention, blood glucose level may also
be monitored by another sensor, such as by examining EKG signals or
nerve signals, and the system responds to insulin demand by
controlling delivery of insulin from an implantable pump or by
stimulating the pancreatic beta cells to enhance insulin production
directly by the pancreas, also as disclosed in referenced Ser. No.
08/876,610.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagram of a human pancreas with electrodes positioned
for use in the system of this invention.
FIG. 2A shows two timing diagrams of beta cell electrical activity
of islets of Langerhans, the upper diagram having a lower burst
duty cycle, while the lower diagram has a higher burst duty cycle;
FIG. 2B is a timing diagram showing in greater detail the features
of a depolarization burst portion of a cycle as depicted in either
diagram of FIG. 2A.
FIG. 3 is a block diagram showing the primary functional components
of a system in accordance with this invention.
FIG. 4 is a flow diagram illustrating the primary steps taken in
stimulating pancreatic beta cells and obtaining glucose level
information from the insulin-producing beta cells, in accordance
with this invention.
FIG. 5A is a simplified flow diagram showing the primary steps of
an automatic implantable closed loop insulin-delivery system in
accordance with this invention; FIG. 5B is a simplified flow
diagram illustrating the primary steps in a system in accordance
with this invention, wherein the system responds to an external
programming command.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to FIG. 1, there is shown a diagram of a human
pancreas, with an indication of some of the primary features of the
pancreas. An implantable device 20 is illustrated, which suitably
contains a stimulus generator and associated electronics, and an
insulin pump. Of course, separate devices can be used, as a matter
of design choice. A sensing lead 22 is illustrated which connects
device 20 to one or more pairs of electrodes illustrated
schematically at 25, 26, for use in stimulating and sensing.
Although not specifically shown, a lead can be positioned into the
pancreatic vein, carrying two or more large electrodes.
Alternately, the system can employ one transvenous electrode and
one epi-pancreatic electrode. Further, as discussed below, the
stimulation and sensing can be done with a transplant of beta cell
islets. An insulin delivery tube 28 is shown for delivery of
insulin into the pancreas, preferably into the portal vein.
Referring to FIG. 2A there are shown two timing diagrams
illustrating the burst behavior of the beta cells of the pancreas,
as described above. In the upper diagram, the duty cycle, defined
as the fraction of the burst duration compared to the overall
depolarization-repolarization cycle, is rather small. This
represents a condition where glucose levels are low to moderate,
and there is relatively little demand for insulin. The lower timing
diagram indicates a situation of greater insulin demand
characterized by a much higher duty cycle, with corresponding
greater burst activity and concurrent insulin production. In an
extreme situation, the burst activity would be virtually
continuous. Referring to FIG. 2B, there is shown a blown up
depiction of the burst or depolarization portion of the beta cell
cycle. It is seen that the onset of depolarization is rather sharp,
followed by relatively high frequency spiking. Toward the end of
the burst period, the spike frequency is seen to diminish, and then
the electrical activity simply tails off. However, the end of the
burst period, as shown in this representation, is sharp enough to
be able to define with substantial accuracy an end of burst time.
As discussed above, the mean spike frequency carries information
reflective of glucose level, but the duration of the burst,
indicated as .DELTA.T.sub.B, is the primary indication insulin
demand, and thus of blood glucose level. As discussed in greater
detail below, either .DELTA.T.sub.B, or .DELTA.T.sub.B as a
fraction of the low frequency depolarization-polarization cycle,
may be used to determine blood glucose level.
Referring now to FIG. 3, there is shown a block diagram of the
primary components of a preferred embodiment of an implantable
system in accordance with this invention. All of the components,
except the heart sensor 40, may be housed in implantable device 20.
A stimulus generator 30 produces stimulus pulses, under control of
the stimulus control block 44, for delivering electric field
stimuli. As used herein, the terms stimulus and pulse refer to
generation of an electric field at a beta cell or nerve site. The
pulses are delivered on lead conductors 22, 24, to the pancreas,
designated by P; or to a transplant, shown as T. The signals sensed
at electrodes 26, 28, i.e., the beta cell electrical activity
signals, are communicated to sense amplifier 32. Amplifier 32 has
suitable timing control and filters for isolating, as well as
possible, the beta cell electrical activity from other interference
signals. The sense signals are processed further with correction
circuit 34, such as an adaptive filter, which subtracts out a QRS
template as generated by block 46 whenever a QRS is detected.
Although not shown in FIG. 3, correction circuit 34 may also
suitably correct for artifacts originating from some other source,
i.e., heart, respiration, stomach, duodemun and uterus. This is
done to cancel out the interference effect of a QRS complex
whenever it occurs during sensing of the beta cell burst. The
output of correction circuit 34 is further processed at 50, where
the time duration of the burst, .DELTA.T.sub.B is determined. Block
50 may also derive a measure of the mean spike frequency of the
burst duration. This information transferred to memory associated
with microprocessor 48, and also is stored at diagnostics block 52.
Microprocessor 48 evaluates the stored data, and generates a
control signal representative of insulin demand, or blood glucose
level. Since insulin secretion, and thus insulin demand is derived
from glucose driven intracellular processes, the terms insulin
demand and glucose level are used interchangeably. The insulin
demand signal which is connected to insulin control block 55, which
produces a control signal for energizing insulin pump 60, which in
turn ejects insulin through delivery tube 28.
A heart sensor 40 is suitably positioned in the vicinity of the
pancreas, as also shown schematically in FIG. 1. The cardiac sensor
output is connected to stimulus timing circuit 42, which times the
QRS signals, and delivers a timing control signal to control block
44, the timing control signal being suitably delayed following the
occurrence of a QRS. By this means, the stimulus generator is
controlled to produce a pulse which is displaced from the QRS,
thereby enabling clear detection of the onset of the beta cell
burst. Thus, when microprocessor 48 delivers an enable signal to
control 44 and there has been a predetermined delay following a
QRS, a stimulus pulse is delivered. The heart sensor output is also
connected to QRS template circuit 46, which generates a template
signal which simulates the interfering QRS signal which would be
sensed by the pancreatic electrodes 26, 28. The QRS template signal
is inputted to correction circuit 34 coincident with sensing of a
QRS complex. Circuit 34 is suitably an adaptive filter.
Additionally, the system illustrated in FIG. 3 may be subject to
external control, as by a programmer 62. Programmer 62 may be any
suitable device, preferably a complex programmer device, although a
simple hand-held magnet which is brought into close proximity to
the implanted device can also be used. The implanted device
contains a transmitter receiver unit 61, which is in two-way
communication with the programmer 62. By this means, the implanted
device can download data held in diagnostic unit 52. Also, it can
pick up initiation signals, to initiate insulin pumping via control
55, or initiate stimulation of the pancreas directly.
The functions illustrated in FIG. 3 are suitably carried out under
software control. Microprocessor 48 includes memory for holding an
appropriate control algorithm and data. It is to be understood that
blocks such as 34, 42, 44, 46, 50 and 52 may be incorporated within
the microprocessor.
Referring to FIG. 4, there is illustrated a flow diagram of the
primary steps taken in accordance with this invention, for
measuring glucose level. It is to be understood that these steps
are suitably carried out under software control. The software
program or routine is initiated at block 68. This initiation may be
done automatically, i.e., every so many minutes. Alternately, it
can be initiated in response to a signal from external programmer
62. Initiation may include setting of reference parameters for
evaluating glucose, e.g., the correlation between .DELTA.T.sub.B
and blood glucose. Following initiation, at 70 the device monitors
beta cell activity over a number of depolarization-repolarization
cycles, to determine as best as possible the approximate onset of a
next burst phase. It is a premise of this routine that some degree
of beta cell activity can be sensed without enhancing stimulation.
If the appropriate onset can be determined, then a stimulus can be
timed for delivery before, but just shortly before, the start of
the next expected spontaneous burst. This enables minimizing the
influence of the stimulus on the burst duration, so that the
subsequently measured duration reflects insulin demand as
accurately as possible. After this, as indicated at 71 the system
waits for a quiet period and for the sensing of a QRS. When a QRS
is detected, the initiation of a stimulus is timed after a delay.
The routine preferably waits until just before the next spontaneous
burst, and delivers a stimulus if the delay following the last QRS
is acceptable to avoid delivery coincident with a QRS. At 72, a
stimulus is delivered to the pancreas, and at 74 the onset of the
beta cell burst is obtained, i.e., the time of the start of the
burst is stored in memory. As indicated at block 75, during the
burst duration, the system continually senses, to measure spike
frequency if available, but primarily to detect the end of the
burst. As indicated at 76, if a burst end has not been found, the
system continues at 77 to monitor the heart sensor output, and
determine whether a QRS is occurring. If a QRS has occurred, the
interference of the QRS signal is corrected out, as indicated at
block 78. Although now shown in FIG. 4, other artifacts are also
corrected with an adaptive filter. When the burst end has been
determined, the routine gets the burst duration .DELTA.T.sub.B, as
indicated at 80. Then, at 82, it is determined whether another
stimulus should be delivered. If yes, the routine loops back to
block 71. Although not shown, a delay may be built in between the
end of one burst and delivery of a next stimulus to produce the
next synchronized burst. At 83, a measure of glucose level is
obtained from the stored value or values of .DELTA.T.sub.B, in
accordance with a predetermined correlation between .DELTA.T.sub.B
and the patient's blood glucose. This correlation is suitably
determined at the time of implant, and programmed into memory; it
can be adjusted by re-programming.
It is to be noted that the purpose of the stimulation is to improve
the accuracy of the measurement. If no initial approximation of
burst onset can be determined without stimulation, i.e., step 70
above, then stimulation can commence at a predetermined rate,
switchably determined by prior testing and stored; the response is
monitored by measuring the depolariztion. The stimulus rate is then
increased until all stimuli yield capture, i.e., initiate a new
burst; when this is achieved, the burst duration is measured.
Alternately, vagal nerve stimulation can be applied to lower the
spontaneous burst rate, enabling the electric field stimulation to
take over at a predetermined lower rate.
Referring now to FIG. 5A, there is shown a simplified flow diagram
of a closed loop control for an automatic implantable system in
accordance with this invention.
At 85, the system carries out ongoing stimulation of the pancreas,
and concurrent measurement of the beta cell activity, according to
the illustrative routine of FIG. 4. At 86, the measured data is
processed and a determination is made as to whether insulin is to
be delivered. For example, if the blood glucose measure derived
from .DELTA.T.sub.B, and/or any other parameters of the sensed
beta-cell signal, is greater than a stored value, then inulin is
indicated. If yes, as indicated at 88, the insulin pump is
controlled to deliver insulin to the patient. Alternately, or in
addition to delivering insulin through an implanted pump, the
pancreas can be stimulated so as to increase endogenous pancreatic
insulin production.
At FIG. 5B, there is shown a simplified flow diagram of the primary
steps of an alternate embodiment where the implanted device
responds to an external command. The external command is received
at 90, either from a programmer which communicates with telemetry
or from a simpler device such as a hand held magnet. When a signal
is received, the stimulate-measure routine of FIG. 4 is initiated
and carried out, as illustrated at 91. After completion of this
measurement routine, at 93 the device determines whether an insulin
response is indicated. If yes, at 94, insulin is provided, either
by delivery from an implanted pump, or by stimulating the pancreas
so as to induce greater insulin production. See application Ser.
No. 08/876,610, filed on the same date as this application and
titled "System and Method For Enhancement of Glucose Production by
Stimulation of Pancreatic Beta Cells," File No. P-7328. Then, at
95, data concerning the measured glucose level and the response is
stored and/or transmitted to the external programmer, for
evaluation and diagnostic purposes.
The preferred embodiments of the invention have been illustrated in
terms of stimulating the pancreas. However, the invention is
equally applicable to working the stimulation-sensing routine on
transplanted pancreatic beta cells, e.g., transplanted islets of
Langerhans, either allo, auto or xeno type. Thus, in FIG. 3 the
stimulus generator can be connected to deliver stimulus pulses to,
and receive depolarization-repolarization signals from a beta cell
transplant (T), exclusive of the pancreas or together with the
pancreas.
* * * * *